Repeat Testing for C. Diff?
By Jeff Glasheen, MD
Mohan SS, McDermott BP, Parchuri S, et al. Lack of value of repeat stool testing for Clostridium difficile toxin. Am J Med. 2006 Apr;119(4):356.e7-356.e8
Clostridium difficile is a common complication of antibiotic and chemotherapeutic use, especially in hospitalized patients. Yet most nosocomial diarrhea is not caused by C. difficile. Most antibiotics can cause loose stools through changes in the gastrointestinal flora that result in inadequate digestion and absorption of carbohydrates and a resultant osmotic diarrhea. Further, antibiotics such as erythromycin and amoxicillin/clavulanate may result in diarrhea via increases in GI tract motility. While osmotic and motility causes of diarrhea tend to improve with antibiotic discontinuation, C. difficile-associated diarrhea is associated with significant morbidity that often continues until adequately treated.
Thus having a test that differentiates between C. difficile and non-clostridial diarrhea is essential. The most commonly used test is the enzyme immunoassay (EIA) that detects toxins A and B. The sensitivity and specificity of this test has been reported to range between 50%-90% and 70%-95%, respectively. The authors of this paper evaluated the utility of repeat EIA testing in patients with a one negative test in the setting of nosocomial diarrhea associated with antibiotic use.
The authors reviewed 474 sequential EIA tests for C. difficile in 396 patients over a 10-month period at a large university-affiliated community hospital with an EIA sensitivity and specificity of 80%-90% and 80%-95%, respectively. Tests were considered to be “repeat” if they occurred within seven days of the original negative test. Of the 78 repeat tests (16.5% of all tests), only one was positive, resulting in a 0.8% conversion rate. At an institutional cost of $128 per test the total cost of EIA testing over the 10-month period was $60,672. The cost of repeat testing alone was $9,984. The authors conclude that there is limited value—and high cost—in repeat EIA testing and that alternative sources of diarrhea should be sought or we should repeat EIA testing in patients with continued nosocomial diarrhea and a negative EIA test.
While prior studies have shown incremental benefit of retesting for C. difficile with the EIA assay, this study’s authors conclude that repeat “C. difficile testing is not clinically justified and is economically wasteful.” Unfortunately, the authors did not utilize a strong enough research design to defend this statement. From the data presented, all we can conclude is that repeat testing with an EIA assay did not add significant value to the diagnostic workup. The lack of a negative gold standard test, such as the cytotoxin assay or follow up outcomes, such as resolution of diarrhea, leaves the reader pondering if the repeat EIA assays were negative because the patients did not have C. difficile or because the test was not sensitive enough to detect the toxin. The reported sensitivity for the EIA assay used was 80-90%, meaning that 10%-20% of patients with C. difficile disease would have had a false negative test. While a second negative test would lower the likelihood of true disease, it would not lower it enough in a patient with a high pre-test probability of disease to sufficiently rule out the disease such that further testing is indicated.
Additionally, while we can extrapolate that the EIA test was of little utility to the patients studied here, no patient-specific data is presented. Thus it is difficult to determine if our patient population is represented in the study. More knowledge about the patients would allow the reader to use published prediction rules to better delineate how likely it was that this cohort was at high risk for having toxin-mediated diarrhea. Perhaps a more reasonable approach to this clinical conundrum would be to send the repeat stool test for a cytotoxin assay or to treat the patient empirically in situations where either the likelihood of disease or the disease burden is high.